EP1133511B1 - Novel intermediates, process for preparing macrolide antibiotic agent therefrom - Google Patents
Novel intermediates, process for preparing macrolide antibiotic agent therefrom Download PDFInfo
- Publication number
- EP1133511B1 EP1133511B1 EP99958490A EP99958490A EP1133511B1 EP 1133511 B1 EP1133511 B1 EP 1133511B1 EP 99958490 A EP99958490 A EP 99958490A EP 99958490 A EP99958490 A EP 99958490A EP 1133511 B1 EP1133511 B1 EP 1133511B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- oxime
- erythromycin
- compound
- equivalents
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 title description 2
- 229940041033 macrolides Drugs 0.000 title description 2
- 239000000543 intermediate Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 37
- 229960002626 clarithromycin Drugs 0.000 claims abstract description 20
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims abstract description 19
- 229960003276 erythromycin Drugs 0.000 claims abstract description 15
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 13
- 229930006677 Erythromycin A Natural products 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- 150000002923 oximes Chemical class 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 8
- KYTWXIARANQMCA-RWJQBGPGSA-N (3r,4s,5s,6r,7r,9r,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecan-2 Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=NO)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-RWJQBGPGSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- -1 1,3-benzodithiol-2-ylium tetrafluoroborate Chemical compound 0.000 claims description 5
- 229910004878 Na2S2O4 Inorganic materials 0.000 claims description 5
- 229910004879 Na2S2O5 Inorganic materials 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 4
- 230000001035 methylating effect Effects 0.000 claims description 4
- 125000003544 oxime group Chemical group 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 230000011987 methylation Effects 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012022 methylating agents Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- HCMLNPZTRYNCMA-UHFFFAOYSA-N 1,3-benzodithiole Chemical compound C1=CC=C2SCSC2=C1 HCMLNPZTRYNCMA-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 0 CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@](C)[C@@]([C@]1N)OC(C2)OC(C)C(*)C2(C)OClI)OC(C2O)OC(C)CC2N(C)C#N)O)=O)[Mn])O)OC1=O Chemical compound CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@](C)[C@@]([C@]1N)OC(C2)OC(C)C(*)C2(C)OClI)OC(C2O)OC(C)CC2N(C)C#N)O)=O)[Mn])O)OC1=O 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000006260 foam Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- HQEVXECMYKMZLQ-UHFFFAOYSA-N 1,3-benzodithiole-2-sulfonic acid Chemical compound C1=CC=C2SC(S(=O)(=O)O)SC2=C1 HQEVXECMYKMZLQ-UHFFFAOYSA-N 0.000 description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- KYTWXIARANQMCA-PGYIPVOXSA-N (3r,4s,5s,6r,7r,9r,10z,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N\O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-PGYIPVOXSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002574 poison Substances 0.000 description 3
- 231100000614 poison Toxicity 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WGHQUJVDEAGKKT-UHFFFAOYSA-N 1,3-benzodithiol-3-ium Chemical compound C1=CC=C2[S+]=CSC2=C1 WGHQUJVDEAGKKT-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KTVOMLQUDMNZLK-UHFFFAOYSA-N 1-benzothiophene-2-sulfonic acid Chemical class C1=CC=C2SC(S(=O)(=O)O)=CC2=C1 KTVOMLQUDMNZLK-UHFFFAOYSA-N 0.000 description 1
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical group C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a novel process for the preparation of clarithromycin represented by formula (I), which has broad antimicrobial activity as a macrolide antibiotic agent, and a novel intermediate that can be used for its synthesis.
- This process comprises protecting 3'-N,N-dimethylamino group and 2'-OH group of erythromycin 9-oxime derivative, wherein an OH group is protected, with a carbobenzyloxy(Cbz) group and then methylating the hydroxyl group at the 6 position of said compound (see Korean Patent Publication Nos. 91-5898 and 91- 7572).
- this process has the disadvantages that an excess Cbz-Cl that is relatively expensive should be used, and even though the deprotection is carried out by the hydrogen reaction, this reaction is not completed on account of the catalytic poison.
- This process comprises protecting 3'-N,N-dimethylamino group of erythromycin 9-oxime derivative, wherein an OH group is protected, with a quaternary salt of an identical group (for example, benzyl group)(see Korean Patent Publication No.91-2142). Since the deprotection in this process is also carried out by using hydrogen as in process 1, it has the disadvantage that the reaction is not completed on account of the catalytic poison as in Process 1.
- This process may be represented by the following scheme:
- This process comprises protecting an oxime of erythromycin 9-oxime derivative with a benzyl or ketal derivative, and protecting 2'-OH group and 4'-OH group of said compound with substituted silyl groups, and then methylating a 6-OH group of said compound, and finally deprotecting a protecting group of 9-oxime and trimethylsilyl group of said 2'-O- and 4"-O- groups of said compound simultaneously in a relatively short step to obtain the desired compound (see Korean Patent Publication Nos. 95-9367 and 96-434).
- the 9-oxime derivative used in the trimethylsilylation of 2'-OH and 4'-OH groups should be used in the salt free form. This process is represented by the following scheme:
- the yield of clarithromycin synthesized from an erythromycin A is about 45 to 50%.
- a benzyl derivative is used to protect an oxime for the above reaction schemes, it is difficult to perform such lengthy reactions since the deprotection is carried out by using hydrogen.
- Another shortcoming is that the ketal derivative, which is used to protect an oxime, has to be used excessively (with about 2 to 3 equivalents) and the total reaction time is rather lengthy. Despite of such shortcoming, the ketal derivative and trimethylsilyl groups can be simultaneously eliminated by an acid treatment.
- Y 1 and Y 2 represent hydrogen atoms or trimethylsilyl groups.
- the present invention provides the compound of the formula (III) (Y 1 and Y 2 are trimethylsilyl groups) crystallized in the mixed solvent comprising 5 to 10 parts by weight of acetone and 1 to 5 parts by weight of water.
- the ratio of the compound of said formula (III) and acetone is 2: 1.
- step 1 is carried out by reacting an equivalent of erythromycin A 9-oxime representing the above formula (II) or hydrochloride thereof with 1 to 2 equivalents of BDTF in an aprotic nonpolar organic solvent in the presence of 1 to 2 equivalents of pyridine to form erythromycin A-9-O-BDT derivative of the above formula (III)' having an oxime group, which is protected with 1, 3-benzodithiol-2-ylium (BDT) group.
- Step 2 is carried out by reacting the resulting compound of the formula (III)' in the above step 1 with 3 to 5 equivalents of hexamethylsilazane (HMDS) in the presence of salts such as ammonium chloride, pyridine hydrochloride, pyridine, or p-toluene sulfonate to form 2'-O-, 4"-O-bitrimethylsilerythromycin A 9-O-BDT oxime derivative of the above formula (V).
- salts such as ammonium chloride, pyridine hydrochloride, pyridine, or p-toluene sulfonate
- a methylation of the compound of the above formula (V) at 6-OH group is carried out in an aprotic polar solvent (such as DMSO or DMF), or a mixture ratio of 1:1 of said aprotic polar solvent and TMF, or a mixture ratio of 2:2:0.3 of said aprotic solvent, TMF and a non-polar organic solvent (such as isopropylether or t-butylethylether) in an amount of 5 to 10 times that of the compound of the above formula (V) to synthesize the formula (VII).
- an aprotic polar solvent such as DMSO or DMF
- TMF a mixture ratio of 1:1 of said aprotic polar solvent and TMF
- a non-polar organic solvent such as isopropylether or t-butylethylether
- the reaction which takes about 30 minutes to 2 hours, has to be carried out in the presence of 0 to 2.5 equivalents of Et 3 N, 1 to 3 equivalents of a strong base such as NaH, alkoxide, KOH and NaOH, and 2 to 3 equivalents of a methylating agent namely methyl iodide at a temperature of -5 to 5 °C.
- a strong base such as NaH, alkoxide, KOH and NaOH
- the compound of the above formula (VII) of the present invention is then deprotected by using 1 to 3 equivalents of formic acid (HCO 2 H) and 4 to 8 equivalents of NaHSO 3 , Na 2 SO 3 , Na 2 S 2 O 4 , or Na 2 S 2 O 5 , and ethanol and water ratio of 1:1 in 5 to 10 parts by weight of the mixed solvent of 1:1 of ethanol and water by refluxing with heat for 4 hours.
- HCO 2 H formic acid
- NaHSO 3 sodium sulfonic acid
- Na 2 SO 3 Na 2 SO 3
- Na 2 S 2 O 4 Na 2 S 2 O 5
- ethanol and water ratio of 1:1 in 5 to 10 parts by weight of the mixed solvent of 1:1 of ethanol and water by refluxing with heat for 4 hours.
- BDSA which is synthesized by reacting a protective group, BDT, with a deoximizing agent such as NaHSO 3 , Na 2 SO 3 , Na 2 S 2 O 4 , or Na 2 S 2 O 5 in the presence of HCOOH, forms into its salt form, represented as the above formula (I).BDSA when joined with a 3'-N,N-dimethylamino group.
- a deoximizing agent such as NaHSO 3 , Na 2 SO 3 , Na 2 S 2 O 4 , or Na 2 S 2 O 5 in the presence of HCOOH
- oxime is synthesized without having any protection. Clarithromycin is synthesized as a result of a deoximization and an elimination of thrimethylsilyl group in the final step.
- the above formula (I).BDSA is reacted with an inorganic salt such as K 2 CO 3 , Na 2 CO 3 , or KOH to remove BDSA in a neutralizing reaction and finally a pure crystal form of clarithromycin representing the above formula (I) is obtained.
- an inorganic salt such as K 2 CO 3 , Na 2 CO 3 , or KOH
- the neutralising reaction of step 5 is carried out by preparing the solution of the compound of the formula (I).
- BDSA by mixing one part by weight of the said compound and 10 to 20 parts by weight of water or 5 to 10 parts by weight of water and 5 to 10 parts by weight of methanol or ethanol in a mixture ratio of 1:1, and adding 3 to 5 parts by weight of the solvent which includes 1 to 2 parts by weight of an inorganic salt to the said solution.
- 157g(O.2 mole) of erythromycin A 9-oxyme ⁇ HCI and 5.4g(0.1 mole) of ammonium chloride were placed into a 2l flask, and 600ml of dimethylformamide were added thereto.
- 217ml(1mole) of hexamethyldisilazane (HMDS) were slowly added to the mixture, and then stirred at a temperature of 35 to 40°C for 3 hours.
- 30ml of water were added to the mixture, and then stirred for one hour. Thereafter, 600ml of water were further added thereto.
- 150ml of 2N-NaOH were added thereto, and the mixture was then extracted with 600ml of dichloromethane.
- the use of benzyl derivative as a protecting group of oxime makes the process difficult since the deprotection should be carried out by the hydrogenation reaction using the catalyst, and this deprotection is not completed on account of the catalytic poison. Furthermore, in case where the ketal derivative is used as a protecting group of oxime during the deprotection, it has the advantage that a trimethylsilyl group and an oxime may be simultaneously deprotected. However, it also has some disadvantages such as an excessive use of ketal derivative and an extended reaction time.
- the protection of an oxime may easily be carried out in near quantitative manner by using 1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) which is simply synthesized from anthranilic acid.
- BDTF 1,3-benzodithiol-2-ylium tetrafluoroborate
- the said BDTF group used as a protecting group of oxime may be simultaneously removed together with trimethylsilyl group and oxime group when the deprotection is carried out under acidic conditions, it simplifies the process, and it is thus possible to obtain about 52% yield of the desired compound of formula (I) by performing this short process involving erythromycin A.
- a BDTF group that has been used in this present invention is responsible for not only protecting oxime and allowing the selectivity, but also forming a BDSA group by reacting with deoximizing agent such as NaHSO 3 , Na 2 SO 3 , Na 2 S 2 O 4 and Na 2 S 2 O 5 and forming clarithromycin salt that can immediately be extracted from the reaction mixture as crystals to effectively indicate that the purification step can be significantly simplified.
- deoximizing agent such as NaHSO 3 , Na 2 SO 3 , Na 2 S 2 O 4 and Na 2 S 2 O 5
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Abstract
Description
Claims (8)
- An erythromycin A 9-O-benzodithide oxime intermediate useful for synthesis of clarthromycin prepared by reacting erythromycin A 9-Oxime or hydrochloride thereof with 1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) represented by formula (III); wherein, Y1 and Y2 are hydrogen atoms or trimethylsilyl groups.
- The intermediate according to Claim 1, wherein a compound of the above formula (III) (Y1 and Y2 are trimethylsilyl groups) is crystallized in the mixed solvent of 5 to 10 parts by weight of acetone and 1 to 5 parts by weight of water, and the ratio of the resulting crystalline solvate comprising the compound of said formula and acetone in 2:1.
- A process for the preparation of clarithromycin of formula (I), which comprises the steps of:1) reacting an erythromycin A 9-oxime of the following formula (II) or hydrochloride thereof with 1.0 to 1.2 equivalents of 1,3-benzodithiol-2-ylium tetrafluoroborate (BDTF) in an aprotic non polar organic solvent in the presence of 1.0 to 2.0 equivalents of pyridine to synthesize an erythromycin A 9-O-BDT oxime derivative of formula (III)' having an oxime group which is protected with 1,3-benzodithiole (BDT) group, as shown in the following scheme; wherein, MC is methylene dichloride,2) reacting a compound of formula (III)' synthesized in the above step 1) with 3.0 to 5.0 equivalents of hexamethyldisilazane (HMDS) in the presence of salts such as ammonium chloride, pyridine hydrochloride, pyridine or p-toluene sulfonate to form 2'-O-,4"-O-bistrimethylsilylerythromycin A 9-O-BDT derivative of formula (V), as shown in the following scheme;3) methylating a 6-OH group of the compound of formula (V) synthesized in the above step 2) with 2.0 to 3.0 equivalents of methyl iodide in an aprotic polar solvent in the presence of strong base to form 2'-O,-4"-O-bistrimethylsilyl-6-O-methyl-erythromycin A 9-O-BDT oxime derivative of formula (VII) as shown in the following scheme;4) deprotecting the compound of formula (VII) synthesized in the above step 3) to form the following formula (I) .BDSA and;
- The process according to Claim 3, which comprises the steps of adding hexamethyldisilazane (HMDS) to erythromycin A 9-oxime or hydrochloride thereof to form 2'-O-4"-O-bistrimethylsilyl- erythromycin A 9-oxime derivative of the following formula (IV) in place of the above step 1), and reacting 2'-O'-4"-O-bistrimethylsilyl-erythromycin A 9-oxime derivative of said formula (IV) in an aprotic organic solvent in the presence of pyridine with a BDTF to form 2'-O'-4"-O-bistrimethylsilyl-erythromycin A 9-O-BDT-oxime derivative of formula (V) in place of the above step 2), as shown in the following scheme:
- The process according to Claim 3, wherein the methylation of the above step 3) is carried out at a reaction temperature of -5 to 5°C by using an aprotic polar solvent such as DMF or DMSO, a mixture ratio of 1:1 of said aprotic polar solvent and THF, or a mixture of 2:2:0.3 of said aprotic polar solvent, THF and a non-polar organic solvent such as isoproplyether or t-butylmethylether, which is used 5 to 10 times the compound of formula (V), with 1.0 to 3.0 equivalents of a strong base such as KOH, alkoxide and NaH, and 2.0 to 3.0 equivalents of methyl iodide as a methylating agent in the presence of 0 to 2.5 equivalents of Et3N for 30 minutes to 2 hours.
- The process according to Claim 3, wherein the miscible organic solvent in the above step 5) is methanol or ethanol.
- The process according to Claim 3, wherein the deprotection of the above step 4) is carried out by using 1.0 to 3.0 equivalents of formic acid and 4.0 to 8.0 equivalents of NaHSO3, Na2S2O4, Na2S2O5 or Na2SO3 in 5 to 10 parts by weight of the mixture ratio of 1:1 of ethanol and water, and cooled at room temperature before being crystallized.
- The process according to Claim 3, wherein the neutralizing reaction of the above step 5) is carried out by preparing the solution of the compound of the above formula (I). BDSA by mixing one part by weight of said compound and 10 to 20 parts by weight of water or 5 to 10 parts by weight of water and 5 to 10 parts by weight of methanol or ethanol in a mixture ratio of 1:1, and adding 3 to 5 parts by weight of the solvent which includes 1 to 2 parts by weight of an inorganic salt to said solution.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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KR19980050425 | 1998-11-24 | ||
KR9850425 | 1998-11-24 | ||
KR9950802 | 1999-11-16 | ||
KR1019990050802A KR100317907B1 (en) | 1998-11-24 | 1999-11-16 | Novel Intermediates, process for preparing macrolide antibiotic agent therefrom |
PCT/KR1999/000708 WO2000031099A1 (en) | 1998-11-24 | 1999-11-24 | Novel intermediates, process for preparing macrolide antibiotic agent therefrom |
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EP1133511A1 EP1133511A1 (en) | 2001-09-19 |
EP1133511B1 true EP1133511B1 (en) | 2003-03-12 |
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US (1) | US6600025B1 (en) |
EP (1) | EP1133511B1 (en) |
JP (1) | JP3848837B2 (en) |
KR (1) | KR100317907B1 (en) |
CN (1) | CN1354753A (en) |
AT (1) | ATE234321T1 (en) |
AU (1) | AU751874B2 (en) |
BR (1) | BR9915646A (en) |
CA (1) | CA2352162A1 (en) |
CZ (1) | CZ20011803A3 (en) |
DE (1) | DE69905935T2 (en) |
DK (1) | DK1133511T3 (en) |
ES (1) | ES2190275T3 (en) |
HU (1) | HUP0104600A3 (en) |
IL (1) | IL143331A0 (en) |
MX (1) | MXPA01005248A (en) |
PL (1) | PL348607A1 (en) |
PT (1) | PT1133511E (en) |
RU (1) | RU2208615C2 (en) |
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WO (1) | WO2000031099A1 (en) |
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WO2004080391A2 (en) | 2003-03-10 | 2004-09-23 | Optimer Pharmaceuticals, Inc. | Novel antibacterial agents |
ES2221807B1 (en) * | 2003-06-24 | 2005-12-16 | Ercros Industrial, S.A. | A PROCEDURE FOR OBTAINING CLARITROMYCIN. |
US7767797B1 (en) * | 2004-09-30 | 2010-08-03 | Synovo Gmbh | Macrocyclic compounds and methods of use thereof |
US7582611B2 (en) * | 2005-05-24 | 2009-09-01 | Pfizer Inc. | Motilide compounds |
US20070015719A1 (en) * | 2005-07-07 | 2007-01-18 | Elan Pharma International Limited | Nanoparticulate clarithromycin formulations |
US20090054634A1 (en) * | 2007-08-09 | 2009-02-26 | Vinod Kumar Kansal | Process for the preparation of clarithromycin |
US9453042B2 (en) | 2007-10-25 | 2016-09-27 | Cempra Pharmaceuticals, Inc. | Process for the preparation of macrolide antibacterial agents |
WO2010048600A1 (en) | 2008-10-24 | 2010-04-29 | Cempra Pharmaceuticals, Inc. | Methods for treating resistant diseases using triazole containing macrolides |
US9937194B1 (en) | 2009-06-12 | 2018-04-10 | Cempra Pharmaceuticals, Inc. | Compounds and methods for treating inflammatory diseases |
WO2011032052A1 (en) | 2009-09-10 | 2011-03-17 | Cempra Pharmaceuticals, Inc. | Methods for treating malaria, tuberculosis and mac diseases |
DK2550286T3 (en) * | 2010-03-22 | 2016-02-29 | Cempra Pharmaceuticals Inc | CRYSTALLINE FORMS OF A MACROLID AND APPLICATIONS THEREOF |
EP2571506B1 (en) | 2010-05-20 | 2017-05-10 | Cempra Pharmaceuticals, Inc. | Processes for preparing macrolides and ketolides and intermediates therefor |
WO2012034058A1 (en) | 2010-09-10 | 2012-03-15 | Cempra Pharmaceuticals, Inc. | Hydrogen bond forming fluoro ketolides for treating diseases |
RU2658050C2 (en) | 2012-03-27 | 2018-06-19 | Семпра Фармасьютикалз, Инк. | Parenteral formulations for administering macrolide antibiotics |
AU2014239959A1 (en) | 2013-03-14 | 2015-10-01 | Cempra Pharmaceuticals, Inc. | Methods for treating respiratory diseases and formulations therefor |
US9751908B2 (en) | 2013-03-15 | 2017-09-05 | Cempra Pharmaceuticals, Inc. | Convergent processes for preparing macrolide antibacterial agents |
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US5872229A (en) * | 1995-11-21 | 1999-02-16 | Abbott Laboratories | Process for 6-O-alkylation of erythromycin derivatives |
US5719272A (en) * | 1996-04-02 | 1998-02-17 | Abbott Laboratories | 2'-protected 3'-dimethylamine, 9-etheroxime erythromycin A derivatives |
US5864023A (en) * | 1997-02-13 | 1999-01-26 | Abbott Laboratories | 3'-N'oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives |
US5929219A (en) * | 1997-09-10 | 1999-07-27 | Abbott Laboratories | 9-hydrazone and 9-azine erythromycin derivatives and a process of making the same |
IL136089A0 (en) * | 1997-12-01 | 2001-05-20 | Abbott Lab | Chemical synthesis of 6-0-alkyl erythromycin c |
WO1999032500A2 (en) * | 1997-12-22 | 1999-07-01 | Biochemie S.A. | Intermediates in macrolide production |
WO1999040097A1 (en) * | 1998-02-04 | 1999-08-12 | Teva Pharmaceutical Industries Ltd. | Process for making clarithromycin |
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IL143331A0 (en) | 2002-04-21 |
KR100317907B1 (en) | 2001-12-24 |
BR9915646A (en) | 2001-08-07 |
WO2000031099A1 (en) | 2000-06-02 |
PL348607A1 (en) | 2002-06-03 |
MXPA01005248A (en) | 2003-08-19 |
HUP0104600A2 (en) | 2002-03-28 |
AU751874B2 (en) | 2002-08-29 |
ES2190275T3 (en) | 2003-07-16 |
AU1584700A (en) | 2000-06-13 |
PT1133511E (en) | 2003-06-30 |
CA2352162A1 (en) | 2000-06-02 |
JP2002530423A (en) | 2002-09-17 |
RU2208615C2 (en) | 2003-07-20 |
DK1133511T3 (en) | 2003-07-14 |
EP1133511A1 (en) | 2001-09-19 |
TR200101474T2 (en) | 2001-12-21 |
DE69905935T2 (en) | 2003-09-04 |
US6600025B1 (en) | 2003-07-29 |
ATE234321T1 (en) | 2003-03-15 |
HUP0104600A3 (en) | 2003-12-29 |
JP3848837B2 (en) | 2006-11-22 |
DE69905935D1 (en) | 2003-04-17 |
CN1354753A (en) | 2002-06-19 |
KR20000057013A (en) | 2000-09-15 |
CZ20011803A3 (en) | 2001-10-17 |
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